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Increased Expression of Cell Adhesion Molecule P-Selectin in Active Inflammatory Bowel Disease Gut: First Published As 10.1136/Gut.36.3.411 on 1 March 1995

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Increased Expression of Cell Adhesion Molecule P-Selectin in Active Inflammatory Bowel Disease Gut: First Published As 10.1136/Gut.36.3.411 on 1 March 1995 Gut 1995; 36: 411-418 411 Increased expression of cell adhesion molecule P-selectin in active inflammatory bowel disease Gut: first published as 10.1136/gut.36.3.411 on 1 March 1995. Downloaded from G M Schurmann, A E Bishop, P Facer, M Vecchio, J C W Lee, D S Rampton, J M Polak Abstract proposed, entailing margination from the The pathogenic changes of inflammatory centreline of blood flow towards the vascular bowel disease (IBD) depend on migration wall, rolling, tethering to the endothelia, stable of circulating leucocytes into intestinal adhesion, and finally, transendothelial migra- tissues. Although leucocyte rolling and tion.1 Each of these steps involves specific fam- tenuous adhesion are probably regulated ilies of adhesion molecules, which are by inducible selectins on vascular expressed on endothelial cells and on circulat- endothelia, little is known about the ing cells as their counterparts and ligands.2 3 expression of these molecules in Crohn's The selectin family of adhesion molecules, disease and ulcerative colitis. Using which comprises E-selectin, P-selectin, and L- immunohistochemistry on surgically selectin, predominantly mediates the first steps resected specimens, this study investi- of cellular adhesion4 5 and several studies have gated endothelial P-selectin (CD62, gran- shown upregulation of E-selectin on activated ular membrane protein-140) in frozen endothelial cells in a variety oftissues6-8 includ- sections of histologically uninvolved ing the gut in patients with IBD.9 10 Little tissues adjacent to inflammation (Crohn's investigation has been made, however, of P- disease= 10; ulcerative colitis= 10), from selectin in normal and diseased gut, although highly inflamed areas (Crohn's its DNA was cloned and sequenced in 1989.11 disease=20; ulcerative colitis=13), and P-selectin (also known as PADGEM, from normal bowel (n=20). By light CD62, LECAM-3, or granular membrane microscopy, two forms of P-selectin protein-140) is stored in endothelial cells and immunoreactivity were detected that platelets and is released after activation by apparently corresponded ultrastruc- mediators of inflammation,12 allowing these turally to stored and released distribu- cells to bind to their receptor/ligands, the car- http://gut.bmj.com/ tions. Compared with the normal gut, bohydrate structure of sialyl-Lewis X, present there was a 3-7-fold increase of P-selectin on neutrophils and monocytes.13-15 immunoreactivity on veins (p<0.0001), Furthermore, P-selectin binds to CD4+ lym- venules (p<0.0001), and capillaries phocytes,'6 subpopulations of memory cells, (p<0.05) in the highly inflamed gut, with- and natural killer cells.17 Expression of P- out differences between Crohn's disease selectin is upregulated by histamine, thrombin, and ulcerative colitis. In the uninvolved tumour necrosis factor o,12 18 19 and by oxygen on September 26, 2021 by guest. Protected copyright. gut, P-selectin expression was similar to radicals,20 some of which have been shown to that seen in normal controls, except for a be present in excess in IBD.21-23 P-selectin is focal increase of P-selectin in the vicinity expressed also on endothelial cells infected by of small lymphocyte aggregates. The viruses,24 the presence of which has recently dramatic upregulation ofP-selectin in the been reported in IBD.25 inflamed tissue and its potential role in In IBD, we have shown an increased per- Department of Histochemistry, Royal leucocyte trafficking support the concept centage of P-selectin positive platelets in the Postgraduate Medical of P-selectin blocking therapy for the peripheral blood of patients with Crohn's School, London control of active IBD. disease and ulcerative colitis.26 In inflamed G M Schurnann A E Bishop (Gut 1995; 36: 411-418) intestinal tissue, there is a single report of P- P Facer selectin in both Crohn's disease and ulcerative M Vecchio Keywords: inflammatory bowel disease, P-selectin. colitis27 which, however, was confined to J M Polak advanced lesions and provided only limited Department of information about the topography and grade of Medicine, St Mark's The migration of leucocytes into tissues is the P-selectin immunoreactivity. Hospital, London central event in inflammation and in an In this study, we hypothesised that P- C W Lee immune response. In inflammatory bowel selectin is upregulated in the development of Department of disease (IBD), there is a dense intestinal infil- the inflammatory lesion and in active IBD. Gastroenterology, trate of inflammatory and activated immune Upregulated P-selectin could induce the Royal London Hospital, London cells with a differential distribution pattern for adhesion of circulating inflammatory cells and D S Rampton Crohn's disease and ulcerative colitis. For the thus contribute to the genesis of the intestinal cellular cellular infiltrate. Correspondence to: development of the local intestinal Dr G Schurmann, infiltrate, circulating cells must stick to the The aim of the study therefore was to Department of the Histochemistry, Royal intestinal vascular endothelium and transmi- investigate qualitatively and quantitatively Postgraduate Medical grate into the tissue, where the immunoinflam- expression of immunoreactive P-selectin on School, Du Cane Road, matory reaction is created. endothelial cells in both uninvolved and highly London W12 ONN. a cascade of adhesion of inflamed areas of Crohn's disease and ulcera- Accepted for publication Recently, multistep 24 June 1994 circulating cells to endothelial cells has been tive colitis, using light microscopy of operative 412 Schiurmann, Bishop, Facer, Vecchio, Lee, Rampton, Polak TABLE I Clinical and histologicalfeatures of 63 patients with inflammatory bowel disease HISTOLOGICAL ASSESSMENT and 21 control patients Tissues were fixed by immersion in Zamboni's Crohn 's Ulcerative solution (saturated picric acid; 0.1 M phos- disease Controls colitis Controls phate buffer; 2% w/v formalin pH 7.2) and ileum ileum colon colon rinsed in 15% (w/v) sucrose in 0-1 M phos- Gut: first published as 10.1136/gut.36.3.411 on 1 March 1995. Downloaded from Patients phate buffered saline with 0 01% (w/v) sodium Number (male:female) 35 (24:11) 7 (5:2) 28 (16:12) 14 (9:4) Mean age (range) (years) 34 (18-70) 60 (38-81) 39 (28-53) 53 (25-77) azide. Cryostat blocks were prepared and sec- Preoperative therapy tioned at 6 ,um thickness. One section from Glucocorticosteroids 28 0 23 0 Sulphasalazine 4 0 22 0 each sample was stained with haematoxylin and Azathioprine 3 0 10 0 eosin for histological determination of inflam- Operations Resection of ileocolonic anastomosis 2 0 0 0 mation according to a previously published Ileal resection 7 0 0 0 method,28 grading from '0' (non-inflamed) to Ileocaecal resection 26 0 0 0 Right sided colectomy 0 7 0 3 '3' (highly inflamed). Only tissues without Left sided or subtotal colectomy 0 0 3 7 histological signs of inflammation (grade '0') Total colectomy 0 0 25 4 Tissues* were included as 'uninvolved' (Table I). Histological grade of inflammation None (grade 0) 12 7 18 14 Mild inflammation (grade 1) 3 0 8 0 Intermediate (grade 2) 11 0 6 0 IMMUNOCYTOCHEMISTRY High (grade 3) 29 0 16 0 Tissue sections were immunostained using a *=Total numbers of tissue samples studied from study A and Study B. range of antibodies (see Table II) by an indirect immunoperoxidase method29: sections serial to those used for staining P-selectin, were specimens. We also examined the intracellular stained with monoclonal antibody against expression of P-selectin in IBD by electron platelet endothelial cell adhesion molecule-i microscopy. (PECAM-1) for the identification of micro- vessels.30 31 Tissues with P-selectin showing a punctate staining pattern were also immuno- Methods stained for von Willebrand factor on serial sec- tions. Infiltrating mononuclear cells were PATIENTS AND TISSUES further characterised by immunostaining for Surgically resected specimens from a total of CD68 (macrophages), CD3 (T cells), and 35 patients with Crohn's disease and 28 CD25 (interleukin 2 receptor) and CD45RO patients with ulcerative colitis were obtained (memory cells) as markers of T cell activation. within 30 minutes ofremoval. For the first part Sections were counterstained with neutral fast of the study, tissue samples were collected red and mounted with glycerol gelatin. http://gut.bmj.com/ from either macroscopically uninvolved areas at a distance of 2-4 cm from the inflamed area or from the centres of inflammation (study A; ELECTRON MICROSCOPY one sample per case). In addition, to study Pre-embedding transmission electron micro- the expression cell adhesion of molecules at scopic immunohistochemistry was performed different distance from the main lesion within on selected cases of both normal and Crohn's the same patient, up to six samples per disease gut to elucidate the cause of the dif- on September 26, 2021 by guest. Protected copyright. specimen were collected from uninvolved, ferential staining pattern of P-selectin seen intermediate, and severely affected areas from by light microscopy on particular endothelia. each of a further five Crohn's disease patients Serial sections of 40 ,um thickness were cut and and five ulcerative colitis patients (study B; stained as mentioned above, free floating, in a several samples per case). Indications for 12 well tissue culture plate. After staining, the surgery were chronic stenosis or disease refrac- sections were fixed in 1 % (w/v) osmium tetrox- tory to treatment, or both, in Crohn's disease ide for two hours at 4°C, washed in phosphate and longstanding pancolitis or left sided colitis buffered saline, dehydrated in graded ethanols, in ulcerative colitis. Non-inflamed control and flat embedded in epoxy resin on a slide tissues were taken from hemicolectomy speci- covered with an acetate sheet.32 After removal mens resected for cancer, at least 5 cm from of the sheet, the flat embedded sections were the malignancy (n= 17), and from total colec- observed under a light microscope.
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